Tyler Hulett

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Tyler Hulett

Tyler Hulett

@seromics

Decoding immunity. Autoimmunity is far more common than anyone today expects or understands. CSO @cdi_labs

Oregon شامل ہوئے Ocak 2018
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Tyler Hulett
Tyler Hulett@seromics·
Will be the largest antigen-specific atlas of humoral immunity yet-constructed with >16K cancer and aging serum samples. Thank you to @CancerGrand & @casanova_lab for supporting and taking a chance on this.
Ludwig Cancer@Ludwig_Cancer

Congrats to Ludwig Oxford Director Xin Lu and Chi Van Dang, CEO & scientific director of the Ludwig Institute for Cancer Research, who’ve received a Cancer Grand Challenges award as members of the ATLAS team to take on the challenge of “Cancer Avoidance”. bit.ly/3N5Ac77

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Tyler Hulett
Tyler Hulett@seromics·
I actually think it’s more likely to work for other cancers than to have actually worked by that mechanism here (tho it could have and that sparked my thought). It’s just serendipity that the tumor itself bears a target others already use for healthy plasma cell depletion to clear bad autoantibodies. I am quite sure “bad autoantibodies” sometimes contribute to cancer happening and treatments failing and if you found those patients, defined them well, I do expect something like “daratumumab + anti-PD1” to unlock a new level of checkpoint blockade efficacy we don’t yet have access to.
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Tyler Hulett
Tyler Hulett@seromics·
Did the daratumumab *just* destroy the myeloma - or did it *also* knock out a T-cell suppressing autoantibody? Daratumumab depletes long-lived plasma cells via CD38 & potentially-harmful immune-altering autoantibodies - not just the cancer! @casanova_lab
Adam C Palmer@ac_palmer

Sometimes cancer treatments are subject to hype, but here’s an advance that’s been understated: Combining a T-cell engager antibody with daratumumab allowed >80% of people with relapsed or refractory multiple myeloma to go years without progression. Might be *permanent* control

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Arf-PEM-Jansen 🪫
Arf-PEM-Jansen 🪫@dokter_Arf·
@seromics @ryan_czm My suggestion would also be to contact @C_Scheibenbogen They’re planning a few immunotherapy trials for Long Covid and ME CFS I’m pretty sure they would be interested to cooperate as they have done a lot of research in auto antibodies
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Tyler Hulett
Tyler Hulett@seromics·
@BReinfeld @casanova_lab ^ you could prove this via something like the US military study that proved EBV was a prerequisite for multiple sclerosis. People bearing certain autoantibodies (say anti-IFNg) should become much higher risk for acquiring melanoma longitudinally
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Tyler Hulett
Tyler Hulett@seromics·
@BReinfeld @casanova_lab Immune-altering autoabs occur in the young but become more common with age. If involved in failed melanoma surveillance (assuming young and old melanomas have similar immunogenicity) you’d expect the same autoab preceding the tumor in both populations as a risk factor
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Tyler Hulett
Tyler Hulett@seromics·
@aaronmring Yes, familiar with REAP, and imagine you have read studies using HuProt! Tonic autoantibody repertoire change is a *possible confounder* in the above kaplan-meier - but agree unlikely to be the dominant effect.
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Aaron Ring
Aaron Ring@aaronmring·
@seromics AAb impacts are interesting and my lab studies them extensively in this context. Still, I think the more parsimonious explanation is easily enough to explain: Tec is better than chemo and cd3 vs FcR engagement are complementary and synergistic.
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Tyler Hulett
Tyler Hulett@seromics·
@aaronmring Agree. Point more 'oh that COULD be possible' than 'is mechanism.' Are indications anti-CD38+ (partially) resets the otherwise exceptionally stable autoantibody repertoire (pubmed.ncbi.nlm.nih.gov/40703261/) - but would be shocked if anywhere near as thorough as anti-BCMA.
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Aaron Ring
Aaron Ring@aaronmring·
@seromics Probably not. Teclistimab (BCMAxCD3) itself is a strong plasma cell depleter, probably more so than dara. Also immune targeting autoantibodies (including anti-IFN, -IL6, -TL1a, -IL17) enhance immunotherapeutic responses in solid tumors. AAb impacts are not one directional.
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Tyler Hulett
Tyler Hulett@seromics·
@BReinfeld @casanova_lab Agree. More triggered the thought - hm - if applied to an extremely immunogenic tumor… Ipi/Nivo/Dara for metastatic melanoma perhaps? I’d be shocked if many melanomas are permitted to exist without an error of immunity (genetic, tumor-evolved, or acquired autoab).
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Dr. Brad Reinfeld, MD PhD
Dr. Brad Reinfeld, MD PhD@BReinfeld·
@seromics @casanova_lab Difficult to interpret. But a reasonable idea. Dara when combined in the first line with more direct anti-MM therapy BUT no T Cell engager does not have this remarkable tail to the curve. Patients ultimately progress. 95% of these patients did not receive Dara upfront. Early days
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Tyler Hulett
Tyler Hulett@seromics·
Molecular mimicry
Dr. Josef@DrJosefWD

23% of schizophrenia patients in the largest NIMH study ever conducted tested positive for anti-gluten antibodies. In healthy controls it was 3%. We are not talking about a subtle statistical blip. We are talking about a seven-fold difference sitting in the research for years while patients stay on medications that may never fully work for them. Up to 30% of people with schizophrenia may have a dietary root cause. That number should change how every psychiatrist practices.

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Tyler Hulett
Tyler Hulett@seromics·
Go to the GlialCAM/ENBA1 molecular mimic that causes multiple sclerosis. Highlight it on the structure. Good. Optimize length for patient HLA genetics. Order the peptide. No, do not formulate it like our cancer vaccine yesterday -- set all adjuvants to 'tolerize.'
Tyler Hulett tweet media
Tyler Hulett@seromics

"Take the VirScan & human proteome PhIP-Seq results and find the patient-level antiviral antibodies that are also molecular mimic autoimmune. Require both the sequences and raw data to match. Make no mistakes." Claude:

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Tyler Hulett
Tyler Hulett@seromics·
@iskander @sebkrier The story is a poor example -- just the point that everyone on here is suddenly excited about cancer vaccines -- and there would be a way to 'biohack your way' to them in much more clever ways!
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alex rubinsteyn
alex rubinsteyn@iskander·
@seromics @sebkrier Claude is a super power in immuno/oncology research. I just don’t know if this story is a good example of that bc it’s impossible to get details
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Tyler Hulett
Tyler Hulett@seromics·
@curtis_yarvin The 'antigen space' for truly automated-at-scale personalized cancer vaccines is a bit more complex than the given example - but essentially solvable in short timeframes. The harder layer is 'what else is broken' with immunity beyond recognition-alone (also solvable!)
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Curtis Yarvin
Curtis Yarvin@curtis_yarvin·
Oncologists should be free to use molecules the way surgeons use scalpels. You don’t need to submit some government form for a new way to clamp the subclavian vein, or whatever. You just try it. On a human. Probably after practicing on some animals, sure
Eddy Lazzarin 🟠🔭@eddylazzarin

“You guys are overhyping this” “Yes we can cure cancer and do regularly this way” “Yes the primary obstacles are regulatory/liability” uh

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Tyler Hulett
Tyler Hulett@seromics·
@iskander @sebkrier Yeah it's crazy to see this take off - such things ARE automatable in far more clever ways than any reading this are able to perceive. Maybe you should build that... Claude is giving incredible powers to us mere mortals!
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alex rubinsteyn
alex rubinsteyn@iskander·
@sebkrier Most optimistic scenario: they genotyped the dog’s MHCs, fine tuned MHCflurry on new dog epitope data, fixed to a neoantigen pipeline to work well for dogs and then made an unusually effective vaccine More likely: adjuvant effect from irrelevant RNA Most likely: noise
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Tyler Hulett
Tyler Hulett@seromics·
Doing something “in addition” like immunopeptidomics or riboseq on the tumor (ie see what it’s literally translating and presenting on MHC) is likely needed for regularly curative cancer vaccines. And this will often STILL need something else like checkpoint blockade to “pick the lock” of an underlying immunodeficiency induced by the tumor, or acquired and protecting it like an autoantibody.
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Tyler Hulett
Tyler Hulett@seromics·
No if that was true everyone would be flying abroad for concierge cancer vaccines. Antigen instruction is only half the battle - and often very simplistic (ie point mutations - easy to find by simple tumor vs somatic sequencing - likely aren’t the best tumor antigens).
Isaac King 🔍@IsaacKing314

...Am I reading this correctly that this person claims cancer has been effectively cured for a while now, but you're not allowed to buy the cure due to regulatory barriers?

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Tyler Hulett
Tyler Hulett@seromics·
Cancer vaccines are difficult - even custom ones - because “getting immunity to see the tumor” is only half the battle. The real problem often a separate immune-failure (tumor evolved and induced or a separate but helping it like an autoantibody-induced defect in immune function). That said - I do think we are fast approaching the day where better tools + reduced regulation can automate design of individual cancer cures. Cures will need BOTH an “instruction component” (ie cancer vaccine to antigens shared by the tumor and all its metastases - not just the piece you biopsied!) AND an “immune fixing component” - (ie a checkpoint blockade, cytokine, or some other infusion that gets around whatever immune issue is preventing tumor clearance).
arctotherium@arctotherium42

Am I interpreting this Tweet correctly - individualized n=1 mRNA cancer vaccines are trivial to make but are never used in people because you can't do an RCT with one person? This seems like a gigantic regulatory failure.

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Tyler Hulett
Tyler Hulett@seromics·
@LammingLab @exfatloss Imagine you get BCAA-catabolism-specific post-translational modifications --> creates weird structures on long lived proteins in neurons --> autoimmunity to those structures (stressed metabolism, poor clearance thereof, autotoxicity to aged brain)
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Lamming Lab
Lamming Lab@LammingLab·
@exfatloss We previously showed protein restriction also prevents or delays AD pathology in a mouse model of AD. Here, we point to BCAAs being the mediators of this effect. But there is also human data associating BCAAs with AD. Of course we need to eat a certain amount of protein to live!
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Tyler Hulett
Tyler Hulett@seromics·
@TuckerGoodrich Yes exactly age associated autoantibodies knocking out cytokines perhaps cause 20%+ of COVID deaths! The paper I linked. The intent of my post is we should just observe what happens naturally in man - skip the mice - observe what helps and harms.
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Tucker Goodrich
Tucker Goodrich@TuckerGoodrich·
@seromics That's my point. Our immune system weakens as we age, and it's one of the factors that will ultimately kill us. See the massive increase in COVID mortality in the aged. Seems like a bad idea to do it outside of a lab. 🤔
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دریافت کریں

@casanova_lab @dokter_Arf @ryan_czm @C_Scheibenbogen @BReinfeld @aaronmring @iskander @sebkrier